Tuesday, August 19, 2008

New Documents: Merck used Doctors and Patients as “Seeds” to Boost Vioxx Sales

According to a paper published in the current issue of Annals of Internal Medicine, Merck conducted a sham clinical trial whose purpose was to turn 600 physician-researchers into marketing seeds to boost sales of its arthritis medication Vioxx. This study, called the ADVANTAGE trial, was billed by the company as a placebo-controlled study comparing Vioxx with the pain reliever Naproxen. However, according to internal company documents obtained in the course of a trial involving Merck, the research was designed and conducted by the marketing division as a “seeding trial,” intended to induce the researchers and their colleagues to prescribe more Vioxx after the clinical trial was over. (More coverage of this story here and here.)

This new variation on the theme of marketing-disguised-as-science is a little complicated, so I interviewed the lead author on this paper, Kevin Hill, M.D., a former Robert Wood Johnson Clinical Scholar at Yale, about the issue. Dr. Hill is now Addiction Psychiatry Fellow at McLean Hospital

Dr. Carlat: What is a “seeding” trial?

Dr. Hill: A seeding trial is a study that is designed to appear as though it is answering a scientific question but whose true purpose is to market a medication.

Dr. Carlat: But how is this different from any industry-funded trial? Anytime a drug company compares its drug with placebo or another drug, aren’t they planning to use the results to help market their drug?

Dr. Hill: That’s true, but a seeding trial is different. In the usual clinical trial, the goal is to answer an important scientific question about your drug and, perhaps, end up with a scientific finding that is advantageous for your drug. You then take that finding, and advertise it to doctors and patients. So the research study itself is not a marketing activity; the marketing comes after the study is over and you have your findings.

In Merck’s seeding trial, their primary interest was not in assessing the gastrointestinal tolerability of Vioxx, because they already had a sense of it from other research they had done. ADVANTAGE was not necessary to address the question of tolerability.

Dr. Carlat: So what was the point of the trial if they weren’t interested in the findings?

Dr. Hill: The point of the study was to market Vioxx directly to the researchers involved. The ADVANTAGE trial recruited a large number of community physicians—600—as “researchers.” The point was to get Vioxx into the hands of all these doctors very early in the game, before the drug came to market. Merck hoped that these doctors would find Vioxx helpful, and that they would spread a positive marketing message to other doctors by word of mouth. The company also paid these doctors to go to researchers’ meetings, and paid them a substantial amount of money for every patient they recruited. They hoped that this financial arrangement would also induce loyalty to Merck and, indirectly, lead them to prescribe even more Vioxx.

Dr. Carlat: I see. So the “seeds” are the physician/researchers, and the hope is that these seeds grow into a positive buzz for Vioxx among colleagues.

Dr. Hill: Exactly.

Dr. Carlat: It seems like we hear about companies manipulating research in various ways all the time. Why is this a particularly objectionable practice?

Dr. Hill: A number of reasons. First and most importantly, doctors and patients were not told about any of these marketing objectives, so they were not given all of the information about what they were signing up for. Generally, patients choose to participate in clinical trials either because they think they might benefit from a treatment, or because they have an altruistic notion of wanting to help the cause of medical science. But if these patients had been told that the trial was designed in order to boost profits of a drug company, I suspect that many might not have participated. In this case, a lot of people risked their health for marketing purposes, and ADVANTAGE is a particularly poignant example because Vioxx increased their chances of having heart attacks.

A second problem is that, as opposed to most clinical trials, Advantage was conceived and run solely by Merck’s marketing division without any input from Merck’s scientific division. We had access to company documents, and what was striking was how frank they were that this study was a marketing exercise. There was little pretense within the company that this was in the service of clinical science.

Dr. Carlat: What were some of the company documents you saw?

Dr. Hill: One of the most revealing was a memo describing an award given by Merck executives to the those in the marketing division who conducted ADVANTAGE . The award describes the trial, quite blatantly, as a marketing program. They were very proud of how they were able to quickly and efficiently get the medication into doctor’s hands.

[Ed. note: This memo is published in the Annals article. Here is one excerpt in which the research is described:“The objectives were to provide product trial among a key physician group to accelerate uptake of VIOXX as the second entrant in a highly competitive new class and gather data important to this customer group. The trial was designed and executed in the spirit of the Merck marketing principles, as described below."]

Another remarkable document was an email written by Dr. Edward Scolnick, the head of the research division at Merck. He said that this trial was “intellectually redundant,” and lamented how ADVANTAGE could exacerbate an already complicated situation as Merck was addressing the safety of VIOXX.

Dr. Carlat: Did Merck make any effort to track the success of the seeding?

Dr. Hill: Yes. We published some of these documents. For example, they did an analysis 6 months after the launch of Vioxx and found that the Advantage researchers prescribed significantly more Vioxx than a control group of primary care physicians who were not part of the research. They also graded a group of rheumatologists from A+ to D based in part on their use of Merck products.

Dr. Carlat: Do seeding trials still go on?

Dr. Hill: Probably, but we don’t know for sure. We only have documentary evidence for ADVANTAGE. The problem is that they often look like legitimate scientific trials. The only reason we knew Advantage was a seeding trial is because we had access to company documents. Merck went to great lengths to hide the nature of this trial. In one memo, an employee in the marketing division wrote: “It may be a seeding study, but let’s not call it that in our internal documents.”

11 comments:

Sara
said...

One thing I am really picking up on as I learn more and more about medical "research" is that it is all designed to serve shareholder interests rather than those of patients. It's about selling sickness and making money, not about promoting wellness and healing people. Sad, because I don't think medicine was always like this. Third party payments and a dearth of primary physicians actually are part of what drives this or at least allow it to take hold. (Read Overtreated by Shannon Brownlee for more on this.) The patient is really an inconvenient necessity, rather than the focal point, in the process.

This is a poignant example of how industry can be its own worst enemy. While the company's own internal documents show that they did little to hide that this "trial" was for marketing purposes (showing a level of honesty), DC's question of Dr. Hill as to why was this a particularly objectionable practice was very telling: "doctors and patients were not told about any of these marketing objectives."

My question for DC and colleagues is ... had Merck been more frank with trial participants, does anyone have an opinion on whether Annals would have published the paper and would ADVANTAGE have been as objectionable as has been painted. In other words, is this type of marketing allowable, ethically, under any circumstances and however complete the disclosures? Many thanks.

In response to James LaRossa, the answer is no, no, and no. What Merck did was to treat patients as commodities, necessary but expendable in service to their redundant experimercial. It is unethical to subject patients to palpable risk when there is no valid scientific objective. the cynicism of Merck is appalling.

It's kind of scary that so many physicians -- with stratospheric IQ's-- could be duped like this! Makes you wonder: Is anyone safe from this sort of manipulation? And how can drug companies get away with basically lying to so many doctors? What ever happened to informed consent in research-- even if it is an "experimercial"? LOL. I LOVE that term, B. Carroll. Keep 'em coming! It adds a bit of levity to an otherwise sordid practice!

The nine Merck documents cited in the Hill paper, and others, can be viewed at the University of California, San Francisco's Drug Industry Document Archive (http://dida.library.ucsf.edu) by entering "cs:humeston" without the quotations in the query box.

If I were to rate the corruptive tactics performed by big pharmaceutical companies, the intentional corruption of implementing fabricated and unreliable results of clinical trials would be at the top of the list. Pharmaceutical companies manipulate the trials they sponsor because of their power to control others involved in the process largely absent of regulation. This is a matter of requiring authenticity and, more importantly, assuring the safety of the public health. Decades ago, clinical trials were conducted in academic settings that focused on the acquisition of knowledge and the completely objective discovery of novel medicine. Then, in 1980, the Bayh-Dole Act was created, which allowed for such places to profit off of their discoveries that were performed for pharmaceutical companies in the past. This resulted in the creation of for-profit sites, called Contract Research Organizations (CROs), which are composed of community research sites with questionable investigators void of necessary experience or quality regarding their research purpose and ability. Since they are for-profit, the trials conducted at CROs are sponsored by pharmaceutical companies that control and manipulate all aspects of the trial. This coercion is done by various methods of deception in subtle and tacit methods. As a result, research in this manner has been transformed into a method of marketing, which includes altered results of the trial to favor the sponsor’s medication. Their activities are absent of true or applied regulation, and therefore have the autonomy to create whatever they want to benefit the collusive relationship between the site and the sponsor. Further disturbing is that once the trials are completed, the medical articles are then written by ghostwriters, who are not identified and acknowledged by the sponsor, and are not trained in clinical research overall, as they are simply freelance writers. How often ghostwriters are utilized by pharmaceutical companies remains a mystery. This activity removes accountability and authenticity of the fabricated clinical trial even further. The corruptive act is finally completed by the sponsor hiring an author to be placed on the trial that likely had no involvement with the trial, and, along with others, was paid by the sponsor. To have the trial published, the sponsor pays a journal, along with the promise of purchasing thousands of reprints of the study from the journal. Again, how often this process is performed is unknown, yet frequent enough to create hundreds of such false writers and research sites to support the industry. So benefits of medicine studied in such a malicious way can potentially harm patients and their treatment options. The purchased reprints are distributed to the sponsor’s sales force to share the content with prescribers — your doctor.Such misconduct impedes research and the scientific method with frightening ethical and harmful concerns. Our health care treatment with medications is now undetermined in large part in such situations, as well as the objectivity that has been intentionally eliminated regarding the trust in the scientific method in this type of activity illustrated in this article. More now than ever, meds that are removed from the market are given black box warnings. Now I understand why this is occurring.The pharmaceutical industry needs transparency and disclosure in order to correct what we have historically relied upon for conclusive proof — the scientific method. More importantly, research should not be conducted in a manner that the sponsor can interfere in the ways I described in this article. We should call for independent sites with absolutely no involvement with the drug maker. And clearly, regulation has to be enforced not selectively, but in a complete fashion. Public awareness would be a catalyst for this to occur, after initially experiencing a state of total disbelief that such operations actually are conducted by such people, of course. We can no longer be dependent on others for our optimal health. Knowledge is power, and is also possibly a lifesaver.Ethics and Science need to shake hands.– Richard CabotDan Abshear (published on www.brainblogger.com)

Author's note: What has been written has been based on information and belief. There is a similar article validating the claims made above at: www.plos.org

My name is Tina Harris and i would like to show you my personal experience with Vioxx.

I am 40 years old. Have been on Vioxx for 6 months now. I had quit taking Vioxx long before the recall because it was the only new med introduced into my regimen at the time the symptoms started. I was told that if I continued to take it, I would be let go from my job because of inability to perform simple tasks.

I have experienced some of these side effects -vertigo, diarrhea, abdominal pain, respiratory problems and memory loss. I still have memory loss and have gaps in my thinking process where I can't even think of common words I am trying to say, even to this day.